This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cocaine-amphetamine regulated transcript (CART) are neuropeptides involved in the brain's reward/reinforcement circuit. CART peptides have psychostimulant-like effects and may be involved in the rewarding actions of cocaine, amphetamine, and other psychostimulants. The expression of CART mRNA and peptide is strictly regulated. Therefore, the major focus of this project has been to characterize the regulation of CART expression in-vivo in the rat NAc. The hypothesis under investigation is that CART mRNA and peptide expression are regulated via cAMP/PKA/CREB signaling. Experiments are designed to determine, 1) if forskolin injection into the NAc increases CART mRNA and peptide expression, 2) if forskolin's effects on CART expression are mediated through PKA, 3) if manipulating CART gene levels with viral vectors effects the expression of CART mRNA and peptides. By identifying and characterizing the signaling mechanism(s) responsible for regulating expression of CART mRNA and peptide, this project will contribute to the understanding of the brain's reward circuitry and the CART peptide. Rats were infected with HSV viral vectors either over- or under-expressing CREB. Over-expressing CREB increased CART mRNA and peptide whereas uner-expressing CREb decreased CART expression, suggesting that CART regulation is ultimately mediated via CREB signalling. Work is also being conducted on projects to identify and characterize a CART receptor.